Mufaddal Mamawala

Intermediate and Longer-Term Outcomes From a Prospective Active-Surveillance Program for Favorable-Risk Prostate Cancer

PURPOSE To assess long-term outcomes of men with favorable-risk prostate cancer in a prospective, active-surveillance program. METHODS Curative intervention was recommended for disease reclassification to higher cancer grade or volume on prostate biopsy. Primary outcomes were overall, cancer-specific, and metastasis-free survival. Secondary outcomes were the cumulative incidence of reclassification and curative intervention. Factors associated with grade reclassification and curative intervention were evaluated in a Cox proportional hazards model. RESULTS A total of 1,298 men (median age, 66 years) with a median follow-up of 5 years (range, 0.01 to 18.00 years) contributed 6,766 person-years of follow-up since 1995. Overall, cancer-specific, and metastasis-free survival rates were 93%, 99.9%, and 99.4%, respectively, at 10 years and 69%, 99.9%, and 99.4%, respectively, at 15 years. The cumulative incidence of grade reclassification was 26% at 10 years and was 31% at 15 years; cumulative incidence of curative intervention was 50% at 10 years and was 57% at 15 years. The median treatment-free survival was 8.5 years (range, 0.01 to 18 years). Factors associated with grade reclassification were older age (hazard ratio [HR], 1.03 for each additional year; 95% CI, 1.01 to 1.06), prostate-specific antigen density (HR, 1.21 per 0.1 unit increase; 95% CI, 1.12 to 1.46), and greater number of positive biopsy cores (HR, 1.47 for each additional positive core; 95% CI, 1.26 to 1.69). Factors associated with intervention were prostate-specific antigen density (HR, 1.38 per 0.1 unit increase; 95% CI, 1.22 to 1.56) and a greater number of positive biopsy cores (HR, 1.35 for one additional positive core; 95% CI, 1.19 to 1.53). CONCLUSION Men with favorable-risk prostate cancer should be informed of the low likelihood of harm from their diagnosis and should be encouraged to consider surveillance rather than curative intervention.

The Role of Multiparametric Magnetic Resonance Imaging/Ultrasound Fusion Biopsy in Active Surveillance

BACKGROUND Multiparametric magnetic resonance imaging (mpMRI)/ultrasound fusion biopsy (targeted biopsy or TB) may improve detection of high-grade cancers when compared to systematic biopsy (SB). OBJECTIVE To assess TB in active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS We retrospectively evaluated SB (12-core sector) and TB among 103 AS men undergoing surveillance biopsy, 54 men undergoing confirmatory biopsy (CB), and 73 men referred for diagnostic biopsy (DB; comparison group). Regions of interest (ROIs) on mpMRI were assigned a PI-RADS score and targeted if the score was ≥3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Detection of Gleason score (GS) ≥7 by TB and SB was the outcome of interest, except in a multivariable model, for which any cancer was the outcome. RESULTS AND LIMITATIONS GS ≥7was detected by either biopsy method in 25 men (24.3%) in the AS group, 12 men (22.2%) in the CB group, and 55 men (75.3%) in the DB group.GS ≥7 was found in 24.3% by SB + TB versus 20.4% by SB in the AS group (p=0.13); in 22.2% by SB + TB versus 16.7% by SB in the CB group (p=0.25); and in 75.3% by SB + TB versus 58.9% by SB in the DB group (p=0.002). The sensitivity for GS ≥7 detection was lower for TB than for SB (p=0.006) in the AS cohort (relative sensitivity ratio 0.33, 95% confidence interval 0.16-0.71). Higher PI-RADS score (4 vs 3, odds ratio [OR] 2.00, p=0.04; 5 vs 3, OR 4.74, p=0.02), lower MRI-estimated prostate volume (OR 1.20 per 10-cm3 lower volume, p=0.01), larger ROI (OR 1.04 per mm, p=0.02), and right-sided ROI (OR 2.27, p=0.01) were associated with finding cancer on TB. A potential limitation is that not all men who presented for biopsy underwent TB and the urologist was not blinded to MRI results before SB. CONCLUSIONS Owing to the low relative sensitivity of mpMRI for detection of GS ≥7 disease, SB still needs to be performed for men on AS. PATIENT SUMMARY This study suggests that image-guided prostate biopsy alone may not be informative for men enrolled in an active surveillance program for prostate cancer.

Pathologic Outcomes in Favorable-risk Prostate Cancer: Comparative Analysis of Men Electing Active Surveillance and Immediate Surgery

BACKGROUND It remains unclear whether men selecting active surveillance (AS) are at increased risk of unfavorable longer term outcomes as compared with men who undergo immediate treatment. OBJECTIVE To compare adverse pathologic outcomes in men with favorable-risk prostate cancer who underwent delayed prostatectomy after surveillance (DPAS) to those who elected immediate prostatectomy (IRP). DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective analysis of a prospective AS registry from 2004 to 2014. From the Johns Hopkins AS program (n = 1298), we identified a subset of men who underwent DPAS (n = 89) and was representative of the entire cohort, not just those that were reclassified to higher risk. These men were compared with men who underwent IRP (n = 3788). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We measured adverse pathologic features (primary Gleason pattern ≥ 4, seminal vesicle invasion [SVI], or lymph node [LN] positivity). Multivariable models were adjusted for age, prostate-specific antigen density, and baseline risk classification. RESULTS AND LIMITATIONS Delayed prostatectomy occurred at a median of 2.0 yr (range: 0.6-9.0) after diagnosis. The DPAS and IRP cohorts demonstrated similar proportions of men with primary Gleason pattern ≥ 4 (17% vs 20%; p = 0.11), SVI (3.3% vs 3.2%; p = 0.53), LN positivity (2.3% vs 1.2%; p = 0.37), and overall adverse pathologic features (21.3% vs 17.0%; p = 0.32). The adjusted odds ratio of adverse pathology was 1.33 (95% confidence interval, 0.82-2.79; p = 0.13) for DPAS as compared with IRP. Limitations include a modest cohort size and a limited number of events. CONCLUSIONS In men with favorable-risk cancer, the decision to undergo AS is not independently associated with adverse pathologic outcomes. PATIENT SUMMARY This report compares men with favorable-risk prostate cancer who elected active surveillance with those who underwent immediate surgery accounting for evidence that approximately one-third of men who choose surveillance will eventually undergo treatment. Our findings suggest that men who are closely followed with surveillance may have similar outcomes to men who elect immediate surgery, but additional research is needed.

Conditional Probability of Reclassification in an Active Surveillance Program for Prostate Cancer

PURPOSE We evaluated the risk of prostate cancer reclassification by time on active surveillance. MATERIALS AND METHODS From 1995 to 2014 we evaluated 557 and 251 men at very low and at low risk, respectively, who were on active surveillance and compliant with prostate biopsies. Our primary study outcome was reclassification to higher risk disease by grade or extent. Freedom from reclassification was estimated using the Kaplan-Meier approach with adjustment for covariates using the Cox proportional hazards model. RESULTS Within the first 2 years of surveillance patient survival free of reclassification by grade (p = 0.20) and by any biopsy criteria (p = 0.25) was similar in men with very low and low risk disease. After 2 years men with low risk disease were 2.4 times more likely to be diagnosed with a Gleason score of greater than 6 than men with very low risk disease (p = 0.002, HR 2.4, 95% CI 1.9-3.5). Additionally, beyond 2 years on surveillance the risk of lifetime reclassification by grade and by any criteria decreased by 30% and 35% (each p <0.0001, HR 0.70, 95% CI 0.60-0.76 and HR 0.65, 95% CI 0.57-0.72, respectively) with each biopsy that showed no reclassification. CONCLUSIONS The reclassification rate during surveillance is not equally distributed across time or risk groups. Due to misclassification at diagnosis the reclassification rate in very low and low risk groups is similar in the first 2 years but differs significantly beyond 2 years. The risk of reclassification decreases with time for each nonreclassifying biopsy beyond 2 years.

Prostate health index density improves detection of clinically‐significant prostate cancer

To explore the utility of Prostate Health Index (PHI) density for the detection of clinically significant prostate cancer (PCa) in a contemporary cohort of men presenting for diagnostic evaluation of PCa.

Risk prediction tool for grade re-classification in men with favourable-risk prostate cancer on active surveillance

To create a nomogram for men on active surveillance (AS) for prediction of grade re‐classification (GR) above Gleason score 6 (Grade group >2) at surveillance biopsy.

Longitudinal assessment of urinary PCA3 for predicting prostate cancer grade reclassification in favorable-risk men during active surveillance

Background:To assess the utility of urinary prostate cancer antigen 3 (PCA3) as both a one-time and longitudinal measure in men on active surveillance (AS).Methods:The Johns Hopkins AS program monitors men with favorable-risk prostate cancer with serial PSA, digital rectal examination (DRE), prostate magnetic resonance imaging and prostate biopsy. Since 2007, post-DRE urinary specimens have also been routinely obtained. Men with multiple PCA3 measures obtained over ⩾3 years of monitoring were included. Utility of first PCA3 score (fPCA3), subsequent PCA3 (sPCA3) and change in PCA3 were assessed for prediction of Gleason grade reclassification (GR, Gleason score >6) during follow-up.Results:In total, 260 men met study criteria. Median time from enrollment to fPCA3 was 2 years (interquartile range (IQR) 1–3) and from fPCA3 to sPCA3 was 5 years (IQR 4–6). During median follow-up of 6 years (IQR 5–8), 28 men (11%) underwent GR. Men with GR had higher median fPCA3 (48.0 vs 24.5, P=0.007) and sPCA3 (63.5 vs 36.0, P=0.002) than those without GR, while longitudinal change in PCA3 did not differ by GR status (log-normalized rate 0.07 vs 0.06, P=0.53). In a multivariable model including age, risk classification and PSA density, fPCA3 remained significantly associated with GR (log(fPCA3) odds ratio=1.77, P=0.04).Conclusions:PCA3 scores obtained during AS were higher in men who underwent GR, but the rate of change in PCA3 over time did not differ by GR status. PCA3 was a significant predictor of GR in a multivariable model including conventional risk factors, suggesting that PCA3 provides incremental prognostic information in the AS setting.

A Bayesian hierarchical model for prediction of latent health states from multiple data sources with application to active surveillance of prostate cancer

In this article, we present a Bayesian hierarchical model for predicting a latent health state from longitudinal clinical measurements. Model development is motivated by the need to integrate multiple sources of data to improve clinical decisions about whether to remove or irradiate a patients prostate cancer. Existing modeling approaches are extended to accommodate measurement error in cancer state determinations based on biopsied tissue, clinical measurements possibly not missing at random, and informative partial observation of the true state. The proposed model enables estimation of whether an individuals underlying prostate cancer is aggressive, requiring surgery and/or radiation, or indolent, permitting continued surveillance. These individualized predictions can then be communicated to clinicians and patients to inform decision-making. We demonstrate the model with data from a cohort of low-risk prostate cancer patients at Johns Hopkins University and assess predictive accuracy among a subset for whom true cancer state is observed. Simulation studies confirm model performance and explore the impact of adjusting for informative missingness on true state predictions. R code is provided in an online supplement and at http://github.com/rycoley/prediction-prostate-surveillance.

Tumor Volume on Biopsy of Low Risk Prostate Cancer Managed with Active Surveillance

Purpose: Contemporary clinical guidelines recommend active surveillance of men with low risk prostate cancer. Low risk disease spans any potential volume of Gleason score 6 cancer without sufficient attention to tumor volume in the past. Therefore, we compared tumor characteristics in men at low risk on active surveillance to men treated with radical prostatectomy. Materials and Methods: We evaluated an institutional cohort of 1,633 men with very low risk disease (clinical stage T1c, prostate specific antigen density less than 0.15 ng/ml/cm3, 2 or more positive cores and 50% or greater core involvement) and low risk disease (clinical stage T2a or less, prostate specific antigen less than 10 ng/ml and Gleason score 6 or less). Among patients at low risk we calculated the proportion who failed to meet very low risk volume criteria (greater than 2 positive cores or greater than 50% core involvement). Clinical and pathological metrics in the active surveillance cohort were compared to those in a cohort of men at low risk who underwent radical prostatectomy in the current era of 2011 to 2016. Results: In the active surveillance cohort 1,119 men (69%) met very low risk criteria and 514 (31%) had low risk disease. In the low risk population only 138 men (27%) harbored higher volume cancer exceeding very low risk criteria compared to 815 (82%) at low risk who underwent radical prostatectomy (p <0.001). Overall the low risk active surveillance population had fewer positive biopsy cores (median 1 vs 3, p <0.001) and a lower maximum percent of core involvement (median 10% vs 40%, p <0.001) compared to patients at low risk who underwent radical prostatectomy. Conclusions: Data supporting the safety of active surveillance in men at low risk at our institution were derived from a distinct subgroup harboring a limited cancer volume. Until acceptable outcomes are confirmed for higher volume tumors it is important to remain mindful of these limitations before broadly recommending active surveillance to all low risk men.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer

Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa.